Palladium-catalyzed asymmetric umpolung allylation of imines with allylic alcohols

Article abstract of DOI:10.1016/j.tetasy.2010.03.003

A palladium-catalyzed asymmetric umpolung allylation reaction of imines with allylic alcohols has been developed. In the presence of chiral spiro phosphoramidite ligand 4, the allylation was accomplished with high yields and good enantioselectivities. The use of highly stable and easily available allylic alcohols instead of allylic metal reagents facilitated the preparation of chiral homoallylic amines.

Full text of DOI:10.1016/j.tetasy.2010.03.003

Tetrahedron: Asymmetry 21 (2010) 1216–1220
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Palladium-catalyzed asymmetric umpolung allylation of imines
with allylic alcohols
*
Xiang-Chen Qiao, Shou-Fei Zhu, Wang-Qiao Chen, Qi-Lin Zhou
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium-catalyzed asymmetric umpolung allylation reaction of imines with allylic alcohols has been
developed. In the presence of chiral spiro phosphoramidite ligand 4, the allylation was accomplished with
high yields and good enantioselectivities. The use of highly stable and easily available allylic alcohols
instead of allylic metal reagents facilitated the preparation of chiral homoallylic amines.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 11 January 2010
Accepted 3 March 2010
Available online 13 April 2010
Dedicated to Professor Henri Kagan, a
pioneer of asymmetric synthesis, on the
occasion of his 80th birthday
1. Introduction
a. previous works
R2
R2
HN
chiral catalyst
3.6 eq. Et3B
Chiral homoallylic amines are amongst the most versatile
intermediates in organic synthesis and are ubiquitous motifs in
bioactive nature products and pharmaceuticals.1 The transition
metal-catalyzed nucleophilic allylation of imines represents one
of the most powerful protocols for the preparation of chiral homo-
allylic amines. Although a large number of efficient chiral transi-
tion metal catalysts have been developed for the highly
enantioselective allylation of carbonyl compounds,2 only a few cat-
alytic asymmetric allylations of imines have been developed.
Moreover, all transition metal-catalyzed enantioselective allyla-
tions of imines use allylic metal reagents such as stannanes,3 si-
lanes,4 and boranes5 (Scheme 1, part a). All allylic metals require
a multi-step preparation and generally are either air or moisture
sensitive, limiting their wide application in organic synthesis. Thus,
the search for more stable and available allylating reagents instead
of commonly used allylic metals has become one of the major chal-
lenges in catalytic asymmetric nucleophilic allylation reactions and
will advance the usefulness of this important transformation. Over
the past decade, people have developed several efficient catalytic
systems by using allylic halides6 or allylic acetates7 as allylating re-
agents in the asymmetric allylation reactions of aldehydes or even
ketones, however, there is still no efficient transition metal cata-
lysts for the enantioselective allylation of imines in the absence
of allylic metal reagents. In view of availability and stability, the
allylic alcohol is an ideal allylating reagent. The direct use of allylic
alcohols can avoid the transformation of allylic alcohols to their
derivatives bearing a wasteful leaving group, and enhances the
synthetic application of the allylation reaction of imines.
N
MX
R1
*
R1
M = Sn, Si, B
b. this work
R2
R2
N
5 mol% Pd(OAc)2
4a
HN
12 mol% (R)-
dioxane, 60 oC
OH
R1
R1
*
3
2a
1
Scheme 1. Transition metal-catalyzed asymmetric allylation of imines.
Quite recently, several research groups developed the transition
metal-mediated allylation of imines with allylic alcohols, which
demonstrated that the direct use of allylic alcohols as allylating re-
agents in asymmetric allylation of imines is possible.8 Our recent
research revealed that the palladium complexes of chiral spiro
monodentated phosphorous ligands are efficient chiral catalysts
for the allylations of aldehydes and activated ketones with allylic
alcohols via umpolung of p
-allylpalladium species.9 As a continu-
ous effort on the development of allylic alcohols as allylic reagents
in the palladium-catalyzed asymmetric umpolung allylation reac-
tions, we herein report our preliminary studies of the palladium-
catalyzed asymmetric allylation of imines with allylic alcohols
(Scheme 1, part b). By using chiral spiro phosphoramidite ligands,
a variety of homoallylic amines were obtained in high yields with
moderate to good enantioselectivities (up to 81% ee).
2. Results and discussion
The palladium-catalyzed allylation of N-tosyl imine 1a with
allylic alcohol 2a was first studied in THF at 60 °C with 3.6 equiv
* Corresponding author. Tel.: +86 22 2350 0011; fax: +86 22 2350 6177.
E-mail address: qlzhou@nankai.edu.cn (Q.-L. Zhou).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.003

X.-C. Qiao et al. / Tetrahedron: Asymmetry 21 (2010) 1216–1220
1217
of triethylborane as umpolung agent (Table 1). When the catalyst
prepared in situ from palladium acetate and the chiral spiro
monodentated phosphoramidite (R)-4a was used, the allylation
reaction ran smoothly to afford homoallylic amine 3a with excel-
lent yield (91%) and moderate enantioselectivity (66% ee) (entry
1). We then tested various chiral spiro ligands developed in this
laboratory in the allylation reaction. The phosphoramidite ligands
with different amine moieties 4a–4e (R3-N-R4) were firstly evalu-
ated in the allylation reaction. All the spiro phosphoramidite li-
gands with N-alkyl moieties 4a–4d were efficient for the
allylation reaction, while N-phenyl-substituted 4e was less effi-
cient in view of the yield and enantioselectivity (entries 1–5). In
all the tested phosphoramidite, 4a with a dimethylamino group
afforded the best result. The other three types of chiral monoden-
tate phosphorus ligands, including phospholane 5, phosphonite 6,
and phosphite 7, were also evaluated in the allylation reaction,
however, reactivities and enantioselectivities were significantly
lower than those obtained with ligand 4a (entries 6–8). To increase
the enantioselectivity further, the reaction conditions were opti-
mized carefully. Besides palladium acetate, the Pd(0) complexes
Pd(dba)2 gave essentially the same level of enantioselectivity albeit
with lower yield (entry 9). Conversely, the [Pd(C3H5)Cl]2 contain-
ing an inner chloride ligand was ineffective for the allylation of
imines (entry 10). The ether solvents THF, dimethoxyethane
(DME), and dioxane and toluene were suitable for the allylation
reaction. The reaction performed in toluene gave the highest level
of enantioselectivity (72% ee), unfortunately, the yield was lower
(73%). Considering both the yield and the ee value, dioxane was
the best solvent of choice.
Under the optimal reaction conditions, the palladium-catalyzed
allylation of various N-tosyl-protected imines with allylic alcohol
was carried out. The para-substituted benzaldehyde-derived imi-
nes 1b–1f, regardless of the electronic properties of the substitute
groups, were favorable for higher enantioselectivity (Table 2, en-
tries 2–6). When 1c derived from 4-chlorobenzaldehyde was used,
the highest enantioselectivity (80% ee) was obtained with excellent
yield (95%) (entry 3). The ortho-substitution groups of imines had
almost no impact on the reactivities and enantioselectivities of
the allylation reaction (entries 9 and 10). The meta-substitution
groups of imines decreased the enantioselectivities significantly
(entries 7 and 8). Besides the substituted benzaldehyde imines,
the allylation of furan-2-carbaldehyde imine 1k with prop-2-en-
1-ol 2a proceeded smoothly under the standard conditions and
produced the corresponding homoallylic amines with good level
of enantioselectivities (75% ee) (entry 11). The
a,b-unsaturated
aldehyde imine 1l was also a suitable substrate for the allylation
reaction, with 76% ee and 60% yield (entry 12).
Table 2
Palladium-catalyzed asymmetric allylation of imines with allylic alcoholsa
Table 1
3.6 eq. Et3B
5 mol% Pd(OAc)2
R2
R2
Palladium-catalyzed asymmetric allylation of an amine with an allylic alcohol:
HN
*
Optimizing the reaction conditionsa
N
12 mol% (R)-4a
dioxane, 60 oC
OH
R1
R1
Ts
Ts
3
2a
HN
*
N
1
5 mol % [Pd]
12 mol % ligand
OH
Entry
R1
R2
Product
Yield (%)
ee (%)
Et3B, solvent, 60 o
C
1
2b
3
C6H5 1a
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
86
88
95
82
89
94
88
88
93
86
71
60
75
62
92
92
68 (ꢀ)
77 (+)
80 (ꢀ)
79 (ꢀ)
69 (+)
74 (ꢀ)
58 (ꢀ)
46 (ꢀ)
65 (ꢀ)
64 (ꢀ)
75 (S)
76 (ꢀ)
77 (+)
60 (+)
67 (+)
63 (S)
4-FC6H4 1b
4-ClC6H4 1c
4-CF3C6H4 1d
4-MeC6H4 1e
4-MeOC6H4 1f
3-ClC6H4 1g
3-MeC6H4 1h
2-ClC6H4 1i
2-MeOC6H4 1j
2-furyl 1k
(E)-PhCH=CH 1l
cHexyl 1m
C6H5 1n
C6H5 1o
C6H5 1p
2a
3a
1a
4
5b
4a R3 = R4 = Me
4b R3 = R4 = iPr
6
7
8
9
10
11
12
13b
14b,c
15b,c
16c
R3
O
O
P
4c R3 = R4 = cHex
P
N
R4 4d
R -R4 = (CH2)4
3
3 = C6H5, R4 = Me
4e
R
3ja
3ka
3la
5
3ma
4-CF3C6H4SO2
4-MeOC6H4SO2
C6H5SO2
3na
3oa
3pa
O
O
O
P
O
P
O
a
b
c
The reaction conditions were the same as those in Table 1, entry 5.
(S)-4a was used.
6
7
The reaction performed in THF.
Entry
[Pd]
Ligand
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(dba)2
[Pd(C3H5)Cl]2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
(R)-4a
(R)-4b
(R)-4c
(R)-4d
(R)-4e
(R)-5
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DME
Dioxane
Toluene
91
81
86
86
36
50
NRd
28
46
NR
56
86
73
66
58
60
60
33
19
—
34
65
—
The protecting group of the imine strongly affected the reactiv-
ity of the allylation reaction. All the sulfonyl-protected imines
underwent the allylation reaction smoothly (entries 14–16). The
para-trifluoromethyl-substituted sulfonyl-protected imine 1n
exhibited lower reactivity as well as enantioselectivity, while
the para-methoxy counterpart 1o gave slightly higher enantiose-
lectivity.
(R)-6
(R)-7
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(R)-4a
67
68
72
Further studies revealed that allylic alcohols with different
substituent patterns were suitable substrates for the allylation
reaction (Scheme 2). 1-Substituted E-crotyl alcohol 2b (R3 = Me,
R4 = H) and E-cinnamyl alcohol 2c (R3 = Ph, R4 = H) reacted with
N-tosyl imine 1a under the standard reaction conditions to
produce the corresponding homoallylic amines with excellent dia-
stereoselectivities (syn/anti = 10:1 and >99:1) and moderate
a
Reaction conditions: [Pd]/ligand/1a/2a/Et3B = 0.0125/0.03/0.25/0.50/0.9 mmol,
2.0 mL solvent at 60 °C, 48–72 h. TS = p-toluenesulfonyl, dba = (1E,4E)-1,5-diphe-
nylpenta-1,4-dien-3-one.
b
Isolated yield.
Determined by HPLC using a Chiralcel OD-H column.
No reaction.
c
d

1218
X.-C. Qiao et al. / Tetrahedron: Asymmetry 21 (2010) 1216–1220
from sodium benzophenone ketyl. Pd(OAc)2, [Pd(C3H5)Cl]2, and
Ts
Ts
3.6 eq. Et3B
HN
R4
N
5 mol% Pd(OAc)2
12 mol% (S)-4a
R4
Et3B, were purchased from Acros or Aldrich Co. Ltd and used as re-
ceived. Pd2(dba)4 and imines11 were prepared according to the
10
R3
OH
solvent, 60 oC
R3
literature procedures. Chiral spiro phosphorous ligands 4, 5, and
6 were prepared according to the previously reported proce-
dures.12 Ligand 4a and 7 can be purchased from STREM Co. Ltd.
Melting points were measured on a RY-I apparatus and uncor-
rected. 1H, 13C, and 31P NMR spectra were recorded on Varian Mer-
cury 400 MHz or Bruker 300 MHz spectrometers. Chemical shifts (d
values) are reported in ppm downfield from internal Me4Si. Optical
rotations were determined using a Perkin Elmer 341 MC polarim-
eter. Mass spectra were recorded on a VG-7070E or VG ZAB-HS
spectrometer. HPLC analyses were performed on a Hewlett Packard
Model HP 1100 Series or Waters 2996 instruments.
3
1a
2
Ts
Ts
Ts
HN
HN
HN
Ph
Me
3ab
3ad
3ac
67% yield
85% yield
65% yield
syn/anti > 99:1
65% ee for syn
81% ee
syn/anti = 10:1
69% ee for syn
Scheme 2.
4.2. Representative procedure for the palladium-catalyzed
asymmetric allylation of imines with allylic alcohols
enantioselectivities (69% and 65% ee). Moreover, 2-methylprop-3-
en-1-ol 2d (R3 = H, R4 = Me) achieved the highest level of enanti-
oselectivity (81% ee) in the allylation reaction.
A full view of the mechanism is still under study in this labora-
tory. A mechanism was proposed as shown in Scheme 3 to ratio-
To a mixture of Pd(OAc)2 (2.8 mg, 0.0125 mmol) and (R)-4a
(9.8 mg, 0.03 mmol) in an argon-filled Schlenk tube, dioxane
(2.0 mL) was added. After the mixture was stirred at 25 °C for
10 min, N-benzylidene-4-methylbenzenesulfonamide 1a (65 mg,
0.25 mmol), prop-2-en-1-ol 2a (30 mg, 0.5 mmol), and Et3B
(0.9 mL, 1.0 M in hexane, 0.9 mmol) were added sequentially. The
mixture was stirred at 60 °C for 48 h. The reaction mixture was di-
luted with ethyl acetate (20 mL) and the reaction was quenched by
adding 3 g of silica gel. After concentrating under reduced pressure,
the residue was transferred to a silica gel pad and washed with
ethyl acetate/petroleum ether (1:10 to 1:5, v/v) to afford the ally-
lation product.
nalize the ‘umpolung’ of the
p-allylpalladium, which was similar
to the mechanism of allylation of aldehyde.9g In the proposed
mechanism, the transfer of the electron-rich ethyl group from bor-
on to palladium (step b) was thought to be essential to change the
electronic property of the palladium center and enhance the nucle-
ophilicity of allyl ligand to imine. However, a detailed mechanism
is still unclear and further studies are highly desired.
4.2.1. (ꢀ)-N-(1-Phenylbut-3-enyl)-4-methylbenzenesulfonamide
L*
(II)
OX
*L
c
Et3B
b
3aa13
Pd(0)L*2
Pd(II)L*2OX
Pd
White solid, 86% yield, 68% ee. Mp: 79–81 °C. ½a D15
ꢁ
¼ ꢀ60:6 (c
a
0.5, CH2Cl2). 1H NMR (400 MHz, CDCl3) d 7.54 (d, J = 8.0 Hz, 2H),
7.20–7.02 (m, 7H), 5.57–5.42 (m, 1H), 5.08–4.92 (m, 3H), 4.36
(dd, J = 6.4 and 13.2 Hz, 1H), 2.50–2.39 (m, 2H), 2.36 (s, 3H). HPLC
conditions: Chiralcel OD-H column, n-hexane/2-propanol = 95:5,
flow rate = 1.0 mL/min, wavelength = 210 nm, tR = 15.0 min (min-
or), and tR = 20.6 min (major).
X = H or Et2B
ethane,
ethene,
butane, ect.
RC=NTs
Ts
e
Et2B
Ts
N
R
N
Et3B
L*
Pd(II)
Et2Pd(II)L*2
+
*
d
R
Et
4.2.2. N-(1-(4-Fluorophenyl)but-3-enyl)-4-methylbenzenesulfona-
mide 3ba14
Scheme 3. Proposed mechanism.
White solid, 88% yield, 77% ee. Mp: 66–77 °C. ½a D19
¼ þ55:2 (c
ꢁ
0.5, CH2Cl2). 1H NMR (400 MHz, CDCl3) d 7.54 (d, J = 8.4 Hz, 2H),
7.15 (d, J = 8.4 Hz, 2H), 7.06–7.03 (m, 2H), 6.89–6.82 (m, 2H),
5.54–5.44 (m, 1H), 5.13 (d, J = 6.4 Hz, 1H), 5.07–5.03 (m, 2H),
4.35 (q, J = 6.8 Hz, 1H), 2.47–2.41 (m, 2H), 2.38 (s, 3H). HPLC condi-
tions: Chiralcel OD-H column, n-hexane/2-propanol = 95:5, flow
rate = 1.0 mL/min, wavelength = 210 nm, tR = 18.1 min (major),
and tR = 22.9 min (minor).
3. Conclusion
In conclusion, a palladium-catalyzed asymmetric umpolung
allylation of imines, using allylic alcohols as allylic reagents,
was developed. The palladium complexes of spiro monodentated
phosphoramidites were efficient catalysts for this transformation,
producing homoallylic amines with good to excellent yields and
moderate to good enantioselectivities. The present allylation
reaction is one of the few asymmetric allylations via the umpo-
4.2.3. N-(1-(4-Chlorophenyl)but-3-enyl)-4-methylbenzenesulf-
onamide 3ca15
White solid, 95% yield, 80% ee. Mp: 118–120 °C. ½a D18
¼ ꢀ80:4 (c
ꢁ
0.5, CH2Cl2). 1H NMR (400 MHz, CDCl3) d 7.52 (d, J = 8.0 Hz, 2H),
7.20–7.06 (br, 4H), 7.04–6.90 (m, 2H), 5.52–5.40 (m, 1H), 5.32
(m, 1H), 5.10–5.00 (m, 2H), 4.32 (dd, J = 6.4 and 12.8 Hz, 1H),
2.54–2.30 (m, 5H). HPLC conditions: Chiralcel OD-H column, n-
hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, wavelength =
210 nm, tR = 10.4 min (minor), and tR = 12.6 min (major).
lung of
p-allylpalladium. The direct use of stable and readily
available allylic alcohols instead of allylic metal reagents ex-
panded upon in the application of asymmetric allylation of
imines.
4. Experimental
4.1. General methods
4.2.4. N-(1-(4-Trifluoromethylphenyl)but-3-enyl)-4-methylben-
zenesulfonamide 3da
White solid, 82% yield, 79% ee. Mp: 118–120 °C. ½a D18
¼ ꢀ58:6 (c
ꢁ
All reactions and manipulations were performed using standard
Schlenk techniques. THF, DME, dioxane, and toluene were distilled
0.5, CH2Cl2). 1H NMR (400 MHz, CDCl3) d 7.50 (d, J = 8.0 Hz, 2H),

X.-C. Qiao et al. / Tetrahedron: Asymmetry 21 (2010) 1216–1220
1219
7.36 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz,
2H), 5.56–5.47 (m, 2H), 5.07–5.03 (m, 2H), 4.44 (dd, J = 6.8 and
13.6 Hz, 1H), 2.49–2.39 (m, 2H), 2.34 (s, 3H). 13C NMR (100 MHz,
CDCl3) d 144.3, 143.4, 137.1, 132.4, 129.3, 127.1, 125.1, 119.7,
56.9, 41.5, 21.3. ESI-HRMS Calcd for [C18H18F3NO2SNa, M+Na]+:
392.0903. Found: 392.0898. HPLC conditions: Chiralcel OD-H col-
umn, n-hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, wave-
length = 210 nm, tR = 9.6 min (minor), and tR = 11.8 min (major).
ane/2-propanol = 90:10, flow rate = 1.0 mL/min, wavelength =
210 nm, tR = 10.3 min (minor), and tR = 12.9 min (major).
4.2.10. N-(1-(2-Methoxyphenyl)but-3-enyl)-4-methylbenzene-
sulfonamide 3ja
Viscous oil, 86% yield, 64% ee. ½a D18
ꢁ
¼ ꢀ26:0 (c 1.6, CH2Cl2). 1H
NMR (400 MHz, CDCl3)
d 7.47 (d, J = 8.0 Hz, 2H), 7.07 (t,
J = 7.2 Hz, 1H), 7.01 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 7.2 Hz, 1H),
6.70 (t, J = 7.2 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 5.60–5.54 (m, 2H),
5.00–4.96 (m, 2H), 4.45 (dd, J = 7.2 and 16.4 Hz, 1H), 3.71 (s, 3H),
2.60–2.43 (m, 2H), 2.29 (s, 3H). 13C NMR (100 MHz, CDCl3) d
156.1, 142.6, 137.5, 134.2, 128.9, 128.8, 128.3, 127.4, 126.8,
120.3, 117.8, 110.4, 56.3, 55.0, 40.0, 21.3. ESI-HRMS Calcd for
[C18H21NO3SNa, M+Na]+: 354.1134. Found: 354.1127. HPLC condi-
tions: Chiralcel OD-H column, n-hexane/2-propanol = 90:10, flow
rate = 1.0 mL/min, wavelength = 210 nm, tR = 10.1 min (minor),
and tR = 12.7 min (major).
4.2.5. N-(1-(4-Methylphenyl)but-3-enyl)-4-methylbenzenesulf-
onamide 3ea13
White solid, 89% yield, 69% ee. Mp: 120–121 °C. ½a D19
¼ þ66:4 (c
ꢁ
0.5, CH2Cl2). 1H NMR (400 MHz, CDCl3) d 7.56 (d, J = 8.0 Hz, 2H),
7.14 (d, J = 8.0 Hz, 2H), 6.97 (dd, J = 8.0 and 12.8 Hz, 4H), 5.55–
5.45 (m, 1H), 5.06–5.02 (m, 2H), 4.96–4.92 (m, 1H), 4.31 (q,
J = 6.8 Hz, 1H), 2.50–2.40 (m, 2H), 2.37 (s, 3H), 2.27 (s, 3H). HPLC
conditions: Chiralcel OD-H column, n-hexane/2-propanol = 95:5,
flow rate = 1.0 mL/min, wavelength = 210 nm, tR = 14.1 min (ma-
jor), and tR = 18.2 min (minor).
4.2.11. N-(1-(Furan-2-yl)but-3-enyl)-4-methylbenzenesulfon-
amide 3ka16
4.2.6. N-(1-(4-Methoxyphenyl)but-3-enyl)-4-methylbenzene-
White solid, 71% yield, 75% ee. Mp: 63–65 °C. ½a D18
ꢁ
¼ ꢀ44:2 (c
¼ ꢀ74:8 (c
sulfonamide 3fa15
0.5, CH2Cl2) and ½a D15
ꢁ
¼ ꢀ43:6 (c 0.5, CHCl3) [lit.16
½ ꢁ
a 2D3
White solid, 94% yield, 74% ee. Mp: 88–90 °C. ½a D18
ꢁ
¼ ꢀ69:6 (c
0.78, CHCl3) for (S)-enantiomer]. 1H NMR (400 MHz, CDCl3) d
7.62 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.12 (s, 1H), 6.09
(s, 1H), 5.94 (d, J = 2.8 Hz, 1H), 5.59–5.48 (m, 1H), 5.40 (d,
J = 8.4 Hz, 1H), 5.03–4.90 (m, 2H), 4.70 (dd, J = 6.8 and 14.8 Hz,
1H), 2.57–2.42 (m, 2H), 2.36 (s, 3H). HPLC conditions: Chiralcel
OD-H column, n-hexane/2-propanol = 90:10, flow rate = 1.0 mL/
min, wavelength = 225 nm, tR = 8.6 min for (R)-enantiomer, and
tR = 10.3 min for (S)-enantiomer.
0.5, CH2Cl2). 1H NMR (400 MHz, CDCl3) d 7.54 (d, J = 8.0 Hz, 2H),
7.15 (d, J = 7.6 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.8 Hz,
2H), 5.55–5.43 (m, 1H), 5.08–5.00 (m, 2H), 4.87 (d, J = 6.0 Hz,
1H), 4.30 (dd, J = 6.4 and 13.2 Hz, 1H), 3.75 (s, 3H), 2.46–2.34 (m,
5H). HPLC conditions: Chiralcel OD-H column, n-hexane/2-propa-
nol = 90:10, flow rate = 1.0 mL/min, wavelength = 225 nm, tR =
14.2 min (minor), and tR = 16.0 min (major).
4.2.7. N-(1-(3-Chlorophenyl)but-3-enyl)-4-methylbenzenesulf-
4.2.12. (E)-N-(1-Phenylhexa-1,5-diene-3-yl)-4-methylbenzene-
onamide 3ga
sulfonamide 3la13
Viscous oil, 88% yield, 58% ee. ½a D18
ꢁ
¼ ꢀ45:4 (c 1.8, CH2Cl2). 1H
Viscous oil, 60% yield, 76% ee. ½a D18
ꢁ
¼ ꢀ91:2 (c 1.2, CH2Cl2). 1H
NMR (400 MHz, CDCl3) d 7.54 (d, J = 8.0 Hz, 2H), 7.14–7.09 (m,
4H), 7.01–6.94 (m, 2H), 5.55–5.44 (m, 1H), 5.41 (d, J = 6.8 Hz, 1H),
5.07–5.03 (m, 2H), 4.34 (dd, J = 6.8 and 13.6 Hz, 1H), 2.46–2.38
(m, 2H), 2.36 (s, 3H). 13C NMR (100 MHz, CDCl3) d 143.3, 142.3,
137.1, 134.1, 132.6, 129.6, 129.3, 127.3, 127.0, 126.8, 124.8, 119.5,
56.7, 41.6, 21.4. ESI-HRMS Calcd for [C17H18ClNO2SNa, M+Na]+:
358.0639. Found: 358.0645. HPLC conditions: Chiralcel OD-H col-
umn, n-hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, wave-
length = 210 nm, tR = 9.2 min (minor), and tR = 12.7 min (major).
NMR (400 MHz, CDCl3) d 7.76 (d, J = 8.0 Hz, 2H), 7.26–7.10 (m,
7H), 6.26 (d, J = 16.0 Hz, 1H), 5.80 (q, J = 7.6 Hz, 1H), 5.71–5.60
(m, 1H), 5.26 (d, J = 7.6 Hz, 1H), 5.13–5.00 (m, 2H), 4.06–3.97 (m,
1H), 2.38–2.23 (m, 5H). HPLC conditions: Chiralcel OD-H column,
n-hexane/2-propanol = 95:5, flow rate = 1.0 mL/min, wavelength =
210 nm, tR = 23.6 min (major), and tR = 26.9 min (minor).
4.2.13. N-(1-Cyclohexylbut-3-enyl)-4-methylbenzenesulfon-
amide 3ma
White solid, 75% yield, 77% ee. Mp = 89–90 °C. ½a D19
¼ þ8:8 (c
ꢁ
4.2.8. N-(1-(3-Methylphenyl)but-3-enyl)-4-methylbenzenesulf-
0.5, CH2Cl2). 1H NMR (400 MHz, CDCl3) d 7.68 (d, J = 8.0 Hz, 2H),
7.21 (d, J = 8.0 Hz, 2H), 5.46–5.35 (m, 1H), 4.88–4.81 (m, 2H),
4.66 (d, J = 8.8 Hz, 1H), 3.06–2.99 (m, 1H), 2.35 (s, 3H), 1.99 (t,
J = 6.4 Hz, 2H), 1.63–1.48 (m, 5H), 1.33–1.26 (m, 1H), 1.10–0.77
(m, 5H). 13C NMR (100 MHz, CDCl3) d 142.1, 137.4, 132.7, 128.5,
126.1, 117.3, 57.1, 39.7, 34.9, 28.1, 27.4, 25.3, 25.1, 20.5. ESI-HRMS
Calcd for [C17H25NO2SNa, M+Na]+: 330.1498. Found: 330.1500.
HPLC conditions: Chiralcel OD-H column, n-hexane/2-propa-
nol = 98:2, flow rate = 1.0 mL/min, wavelength = 210 nm, tR =
17.0 min (minor), and tR = 20.0 min (major).
onamide 3ha
Viscous oil, 88% yield, 46% ee. ½a D18
ꢁ
¼ ꢀ36:5 (c 1.75, CH2Cl2). 1H
NMR (400 MHz, CDCl3) d 7.54 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz,
2H), 7.06 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 6.88 (d,
J = 7.6 Hz, 1H), 6.78 (s, 1H), 5.58–5.47 (m, 1H), 5.21 (br, 1H),
5.07–5.02 (m, 2H), 4.33 (dd, J = 6.8 and 13.6 Hz, 1H), 2.50–2.40
(m, 2H), 2.36 (s, 3H), 2.18 (s, 3H). 13C NMR (100 MHz, CDCl3) d
142.9, 140.1, 137.8, 137.5, 133.2, 129.1, 128.2, 128.0, 127.2,
127.1, 123.6, 119.0, 57.2, 41.8, 21.4, 21.2. ESI-HRMS Calcd for
[C18H21NO2SNa, M+Na]+: 338.1185. Found: 338.1191. HPLC condi-
tions: Chiralcel OD-H column, n-hexane/2-propanol = 90:10, flow
rate = 1.0 mL/min, wavelength = 210 nm, tR = 8.3 min (minor), and
tR = 10.6 min (major).
4.2.14. N-(1-Phenylbut-3-enyl)-4-trifluoromethylbenzenesulf-
onamide 3na
White solid, 62% yield, 60% ee. Mp: 82–84 °C. ½a D15
¼ þ24:6 (c
ꢁ
0.98, CH2Cl2). 1H NMR (400 MHz, CDCl3) d 7.69 (d, J = 8.4 Hz, 2H),
7.51 (d, J = 8.0 Hz, 2H), 7.14–7.07 (m, 3H), 6.99–6.97 (m, 2H),
5.63–5.53 (m, 1H), 5.41 (d, J = 6.8 Hz, 1H), 5.11–5.07 (m, 2H),
4.46 (dd, J = 6.8 and 13.6 Hz, 1H), 2.48 (t, J = 7.2 Hz, 2H). 13C NMR
(100 MHz, CDCl3) d 144.0, 139.4, 133.9 (q), 132.8, 128.4, 127.6,
127.5, 126.6, 125.6 (q), 119.4, 57.6, 41.8. ESI-HRMS Calcd for
[C17H16F3NO2SNa, M+Na]+: 378.0746. Found: 378.0750. HPLC con-
ditions: Chiralcel OD-H column, n-hexane/2-propanol = 90:10,
4.2.9. N-(1-(2-Chlorophenyl)but-3-enyl)-4-methylbenzenesulf-
onamide 3ia15
White solid, 93% yield, 65% ee. Mp: 98–100 °C. ½a D18
¼ ꢀ44:2 (c
ꢁ
0.5, CH2Cl2). 1H NMR (400 MHz, CDCl3) d 7.60 (d, J = 8.0 Hz, 2H),
7.21–7.05 (m, 6H), 5.54–5.43 (m, 1H), 5.36–5.30 (m, 1H), 5.07–
5.01 (m, 2H), 4.80 (dd, J = 7.2 and 13.2 Hz, 1H), 2.50–2.37 (m,
2H), 2.35 (s, 3H). HPLC conditions: Chiralcel OD-H column, n-hex-

1220
X.-C. Qiao et al. / Tetrahedron: Asymmetry 21 (2010) 1216–1220
flow rate = 1.0 mL/min, wavelength = 210 nm, tR = 9.0 min (major),
and tR = 13.4 min (minor).
n-hexane/2-propanol = 95:5, flow rate = 1.0 mL/min, wavelength =
210 nm, tR = 13.8 min (major), and tR = 17.5 min (minor).
4.2.15. N-(1-Phenylbut-3-enyl)-4-methoxybenzenesulfonamide
Acknowledgments
3oa
White solid, 92% yield, 67% ee. Mp: 81–83 °C. ½a D15
ꢁ
¼ þ44:5 (c
We thank the National Natural Science Foundation of China,
the Major Basic Research Development Program (Grant No.
2006CB806106), and the ‘111’ project (B06005) of the Ministry of
Education of China for financial support.
1.58, CH2Cl2). 1H NMR (400 MHz, CDCl3) d 7.61 (d, J = 8.8 Hz, 2H),
7.19–7.12 (m, 3H), 7.09–7.07 (m, 2H), 6.79 (d, J = 8.8 Hz, 2H),
5.59–5.45 (m, 2H), 5.07–5.02 (m, 2H), 4.36 (dd, J = 7.2 and
14.0 Hz, 1H), 3.81 (s, 3H), 2.52–2.40 (m, 2H). 13C NMR (100 MHz,
CDCl3) d 162.6, 140.4, 133.3, 132.1, 129.2, 128.3, 127.3, 126.6,
119.0, 113.8, 57.4, 55.6, 41.9. ESI-HRMS Calcd for [C17H19NO3SNa,
M+Na]+: 340.0978. Found: 340.0977. HPLC conditions: Chiralcel
OD-H column, n-hexane/2-propanol = 90:10, flow rate = 1.0 mL/
min, wavelength = 210 nm, tR = 14.6 min (major), and tR = 19.8 min
(minor).
References
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4.2.16. N-(1-Phenylbut-3-enyl)benzenesulfonamide 3pa3d
White solid, 92% yield, 63% ee. Mp: 88–90 °C. ½a D15
ꢁ
¼ ꢀ45:2 (c
[a] = +47 (c
D
1.55, CH2Cl2) and ½a D15
ꢁ
¼ ꢀ43:4 (c 0.5, CHCl3) [lit.3d
0.27, CHCl3) for (R)-enantiomer with 73% ee]. 1H NMR (400 MHz,
CDCl3) d 7.70–7.66 (m, 2H), 7.47–7.41 (m, 1H), 7.35–7.29 (m,
2H), 7.17–7.11 (m, 3H), 7.10–7.06 (m, 2H), 5.61–5.49 (m, 2H),
5.09–5.00 (m, 2H), 4.42 (dd, J = 6.8 and 12.0 Hz, 1H), 2.54–2.41
(m, 2H). HPLC conditions: Chiralcel OD-H column, n-hexane/2-pro-
panol = 95:5, flow rate = 1.0 mL/min, wavelength = 210 nm, tR =
14.3 min for (R)-enantiomer, and tR = 20.9 min for (S)-enantiomer.
4.2.17. N-(2-Methyl-1-phenylbut-3-enyl)-4-methylbenzene-
sulfonamide 3ab13
White solid, 64% yield, syn/anti = 10:1, 69% ee for syn-isomer.
Mp: 98–101 °C. ½a D19
ꢁ
¼ þ55:4 (c 0.5, CH2Cl2). 1H NMR for syn-iso-
mer (400 MHz, CDCl3) d 7.49 (d, J = 8.0 Hz, 2H), 7.12–7.09 (m,
3H), 7.06 (d, J = 8.4 Hz, 2H), 6.94–6.92 (m, 2H), 5.50–5.41 (m,
1H), 5.13 (br, 1H), 5.04–5.00 (m, 2H), 4.26 (dd, J = 8.4 and 6.0 Hz,
1H), 2.57–2.49 (m, 1H), 2.32 (s, 3H), 0.93 (d, J = 6.8 Hz, 3H). HPLC
conditions: Chiralcel OJ-H column, n-hexane/2-propanol = 90:10,
flow rate = 1.0 mL/min, wavelength = 210 nm, tR = 12.4 min (min-
or), and tR = 29.2 min (major).
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(b) Itoh, J.; Han, S. B.; Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 6313–6316.
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1254–1261; for reviews on umpolung of p-allylpalladium, see: (c) Tamaru, Y. J.
4.2.18. N-(1,2-Diphenylbut-3-enyl)-4-methylbenzenesulfon-
amide 3ac17
Organomet. Chem. 1999, 576, 215–231; (d) Marshall, J. A. Chem. Rev. 2000, 100,
3163–3185; (e) Zanoni, G.; Pontiroli, A.; Marchetti, A.; Vidari, G. Eur. J. Org.
Chem. 2007, 3599–3611; for palladium-catalyzed asymmetric umpolung
allylation with aldehyde developed by other groups, see: (f) Zanoni, G.;
Gladiali, S.; Marchetti, A.; Picoinini, P.; Tredic, I.; Vidari, G. Angew. Chem., Int. Ed.
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2009, 28, 2640–2642.
White solid, 67% yield, syn/anti >99:1, 65% ee for syn-isomer.
Mp: 136–138 °C. ½a D19
ꢁ
¼ þ15:6 (c 0.5, CH2Cl2). 1H NMR for syn-iso-
mer (400 MHz, CDCl3) d 7.37 (d, J = 8.4 Hz, 2H), 7.25–7.23 (m, 3H),
7.16–7.08 (m, 3H), 7.05 (d, J = 8.0 Hz, 2H), 6.96–6.94 (m, 2H), 6.90–
6.88 (m, 2H), 5.84–5.75 (m, 1H), 5.01 (d, J = 10.0 Hz, 1H), 4.88 (d,
J = 17.2 Hz, 1H), 4.76 (d, J = 6.0 Hz, 1H), 4.53 (t, J = 7.0 Hz, 1H),
3.53 (t, J = 8.0 Hz, 1H), 2.34 (s, 3H). HPLC conditions: Chiralcel
OD-H column, n-hexane/2-propanol = 95:5, flow rate = 1.0 mL/
min, wavelength = 210 nm, tR = 17.8 min (minor), and tR = 24.9 min
(major).
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9621–9628.
4.2.19. N-(3-Methyl-1-phenylbut-3-enyl)-4-methylbenzenesulf-
onamide 3ad18
White solid, 85% yield, 81% ee. Mp: 77–79 °C. ½a D19
¼ þ95 (c 0.5,
ꢁ
CH2Cl2). 1H NMR (400 MHz, CDCl3) d 7.52 (d, J = 8.4 Hz, 2H), 7.17–
7.12 (m, 7H), 4.83 (s, 2H), 4.73 (s, 1H), 4.39–4.34 (m, 1H), 2.36–2.35
(m, 5H), 1.52 (s, 3H). HPLC conditions: Chiralcel OD-H column,
17. Miyabe, H.; Yamaoka, Y.; Naito, T.; Takemoto, Y. J. Org. Chem. 2003, 68, 6745–
6751.
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